Presentations discussing brentuximab vedotin (Adcetris®; Seagen/Takeda) presented during the 62nd American Society of Hematology (ASH) Annual, Meeting, and Exposition, held virtually from December 5 – 8, 2020, include five-year updated results from the phase III ECHELON-1 and ECHELON-2 clinical trials. These trials evaluate a combination of brentuximab vedotin plus chemotherapy in frontline advanced-stage classical Hodgkin lymphoma and CD30-expressing frontline peripheral T-cell lymphoma (PTCL), respectively.

There are more than 100 subtypes of non-Hodgkin lymphomas. The disease is broadly divided into two major groups: B-cell lymphomas, which develop from abnormal B-lymphocytes, and T-cell lymphomas, which develop from abnormal T-lymphocytes.

T-cell lymphomas, some of which are extremely rare, can be aggressive or indolent. Peripheral T-cell lymphoma accounts for approximately 10% of non-Hodgkin lymphoma cases in the U.S. and Europe and maybe as high as 24% in parts of Asia.

Antibody-drug Conjugate
Brentuximab vedotin is an antibody-drug conjugate (ADC) directed to CD30, a defining marker of classical Hodgkin lymphoma and expressed on the surface of several types of non-Hodgkin lymphoma, including peripheral T-cell lymphoma.

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The drug includes an anti-CD30 monoclonal antibody which is attached by a protease-cleavable linker to a monomethyl auristatin E (MMAE), a microtubule disrupting agent. The linker system is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing cells.

Five-year follow-up
Historically, a relapse of classical Hodgkin lymphoma (cHL) occurs within the first 5 years.[1]

“After five years of follow-up, an important clinical milestone, both the ECHELON-1 and ECHELON- 2 clinical trials demonstrate that brentuximab vedotin plus chemotherapy resulted in superior and durable outcomes when compared with standard chemotherapy regimens,” said Roger Dansey, M.D., Chief Medical Officer at Seagen.

“As most relapses in Hodgkin lymphoma occur within five years of frontline treatment, the results of the ECHELON-1 study suggest that patients treated with brentuximab vedotin plus chemotherapy are more likely to experience long-term remissions compared to those treated with the ABVD regimen,” Dansey added.

ECHELON-1
The ECHELON-1 clinical trial is evaluating brentuximab vedotin in combination with AVD (Adriamycin [doxorubicin], vinblastine, dacarbazine) compared to ABVD (Adriamycin [doxorubicin], bleomycin, vinblastine, dacarbazine) in patients with Stage III or IV frontline classical HL.

As previously reported, the ECHELON-1 trial achieved its primary endpoint with the combination of brentuximab vedotin plus AVD resulting in a statistically significant improvement in modified progression-free survival (PFS) compared to the control arm of ABVD as assessed by independent review facility (IRF; hazard ratio (HR), 0.77; p=0.035).

A five-year exploratory analysis was conducted to examine PFS outcomes per investigator assessment in the intent-to-treat population of 1,334 patients. Results include:

  • Patients in the brentuximab vedotin plus AVD arm had a 32% reduction in the risk of a progression event compared to patients in the ABVD arm. The five-year PFS rate for patients in the brentuximab vedotin plus AVD arm was 82.2% compared to 75.3% in the ABVD arm, an absolute difference of 6.9% (HR, 0.681 [95% CI: 0.534, 0.867]). Median follow-up time was 60.9 months.
  • Consistent benefit in PFS was observed among patients treated with brentuximab vedotin plus AVD compared with ABVD, independent of disease stage, age and prognostic score.o Consistent improvements compared to ABVD were observed in patients with Stage III (HR, 0.593; [95% CI: 0.385, 0.915]) and Stage IV (HR, 0.731; [95% CI: 0.545, 0.980]) disease.
  • As previously reported for the primary analysis, on the brentuximab vedotin plus AVD arm, peripheral neuropathy events were observed in 67% of patients compared to 43% in the ABVD arm. The five-year update shows that among patients with peripheral neuropathy, 85% in the brentuximab vedotin plus AVD arm and 86% in the ABVD arm reported complete resolution or improvement at last follow-up.
  • There were fewer secondary malignancies in the brentuximab vedotin plus AVD arm. Among 48 patients with reported secondary malignancies, 19 [(nine hematological malignancies and 10 solid tumors)] were in the brentuximab vedotin plus AVD arm and 29 [(15 hematological malignancies and 14 solid tumors)] were in the ABVD arm.
  • There were a higher number of pregnancies in the brentuximab vedotin plus AVD arm compared to the ABVD arm. A total of 150 pregnancies were reported among study participants and their partners, including 89 on the brentuximab vedotin plus AVD arm and 61 on the ABVD arm.

ECHELON-2
The ECHELON-2 clinical trial is evaluating brentuximab vedotin in combination with CHP (cyclophosphamide, Adriamycin [doxorubicin], prednisone) compared to CHOP (cyclophosphamide, Adriamycin [doxorubicin], vincristine, prednisone) in frontline CD30-expressing PTCL.

As previously reported, the ECHELON-2 trial met its primary endpoint with the combination of brentuximab vedotin plus CHP resulting in a statistically significant improvement in PFS versus the control arm of CHOP per blinded independent central review (HR, 0.71; p=0.0110).

A five-year post-hoc exploratory analysis was conducted to examine PFS outcome and overall survival (OS) per investigator assessment in the intent-to-treat population of 452 patients.

The key findings include:

  • Patients in the brentuximab vedotin plus CHP arm had a 30% reduction in the risk of a progression event compared to patients in the CHOP arm. The five-year PFS rate for patients in the brentuximab vedotin plus CHP arm was 51.4% compared to 43% in the CHOP arm, an absolute difference of 8.4% (HR, 0.70 [95% CI: 0.53, 0.91]).
  • OS in the brentuximab vedotin plus CHP arm was improved compared to CHOP (HR=0.72 [95% CI: 0.53, 0.99]). This represents a 28% reduction in the risk of death. Median follow-up time was 66.8 months.
  • Among 316 systemic anaplastic large-cell lymphoma (sALCL) patients on study, patients in the brentuximab vedotin plus CHP arm had a 45% reduction in the risk of a progression event compared to patients in the CHOP arm (HR, 0.55 [95% CI: 0.39, 0.79]). There was a 34% reduction in the risk of death. Median follow-up time for PFS was 42.7 months.
  • Consistent improvement in both PFS and OS was observed among patients treated with brentuximab vedotin plus CHP arm compared to the CHOP arm across the majority of pre-specified subgroups.
  • The five-year update shows that among patients with peripheral neuropathy, 72% in the brentuximab vedotin plus CHP arm and 78% in the CHOP arm reported complete resolution or improvement at last follow-up. For ongoing peripheral neuropathy events, 98% in the brentuximab vedotin plus CHP arm and 98% in the CHOP arm were Grade 1 or 2.

Mediastinal Grey Zone Lymphoma
In addition to ECHELON-1 and ECHELON-2 updates the first results were presented from an ongoing phase II clinical trial evaluating brentuximab vedotin in combination with nivolumab (Opdivo®; Bristol-Myers Squibb) in relapsed or refractory mediastinal gray zone lymphoma, a rare type of non-Hodgkin lymphoma that expresses CD30 with no standard of care.[2]

Grey zone lymphoma, which is sometimes called ‘B-cell lymphoma, unclassifiable’, is a very rare but aggressive or fast-growing B-cell non-Hodgkin lymphoma. This uncommon neoplasm that has clinical features and characteristics of both Hodgkin lymphoma and a type of diffuse large B-cell lymphoma, called primary mediastinal B-cell lymphoma (PMBCL), was initially described in 2005 and recognized in the World Health Organization (WHO) classification as a distinct entity in 2008. [2][3]

In spite of the advances made in immunophenotyping, molecular diagnostics, and more exact morphology-based discrimination, the disease is very difficult to diagnose and treatment decisions remain complex.[4][5]

Although grey zone lymphoma is an aggressive disease that can be difficult to treat, it is potentially curable with standard treatment that includes combination chemotherapy and immunotherapy (chemoimmunotherapy), or in some instances sometimes with radiotherapy and stem cell transplant.

The most common chemotherapy regimens for the treatment of patients with grey zone lymphoma include treatment with one of 3 regimens with cyclophosphamide, doxorubicin, vincristine, and prednisone ± rituximab (CHOP±R), or doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), or dose-adjusted etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and rituximab (DA-EPOCH-R).

Mediastinal gray zone lymphomas feature as a transitional link between classical Hodgkin lymphoma nodular sclerosis (NS) and primary mediastinal large B-cell lymphoma.

CheckMate 436
PD-1 blockade has shown promise in B- and T-cell non-Hodgkin lymphoma. However, many patients with non-Hodgkin lymphomas do not respond or progress after response, and the combination using anti-tumor agents with complementary mechanisms of action and low immunosuppressive impact may result in more frequent and durable responses.

Based on this understanding, researchers developed the phase II CheckMate 436 (NCT02581631), an open-label, single-arm study evaluating nivolumab, a PD-1 immune checkpoint inhibitor that augments T-cell activation and host anti-tumor responses, and brentuximab vedotin.

Brentuximab vedotin induces cell cycle arrest and apoptosis with activity in a range of non-Hodgkin lymphomas. Tumor cells undergoing brentuximab vedotin-induced apoptosis have shown subsequent immune-mediated anti-tumor cytotoxicity. Hence, it was believed that nivolumab and brentuximab vedotin may synergize if combined for the treatment of relapsed/refractory non-Hodgkin lymphomas.

Data from the ongoing CheckMate 436 phase II clinical trial of 10 patients with relapsed or refractory mediastinal gray zone lymphomas who received a treatment combination of brentuximab vedotin plus nivolumab after autologous stem cell transplant or two or more lines of multi-agent chemotherapy if ineligible for transplant were, for the first time, presented during the annual ASH meeting. Patients were treated once every three weeks or until disease progression or unacceptable toxicity. The median age of patients was 35 years.

The Key findings from this study include:

  • Of 10 response-evaluable patients, seven patients (70%) had an objective response, including five patients (50%) with a complete response and two patients (20 percent) with a partial response. Two patients (20%) had progressive disease and in one patient (10%) death occurred prior to disease assessment.
  • Median follow-up time was 12.4 months. Time to complete response was 1.2-4.8 months and the duration was 1.5+ to 3.2+ months before patients were assessed for subsequent therapy. All patients who achieved a complete response underwent a hematopoietic cell transplant and follow-up is ongoing.
  • The most common adverse events of any grade in at least 20% of patients were neutropenia and paresthesia (30% each); thrombocytopenia, anemia, and peripheral sensory neuropathy (20% each). The most common Grade 3 adverse events were neutropenia and thrombocytopenia (10% each). Three patient deaths occurred due to disease progression.

Abstracts
Straus DJ, Dlugosz-Danecka M, Connors JM, Illés Á, Picardi M, Lech-Marańda E, Feldman T, Smolewski P, et al. Brentuximab Vedotin with Chemotherapy for Patients with Previously Untreated, Stage III/IV Classical Hodgkin Lymphoma: 5-Year Update of the ECHELON-1 Study (Abstract #2973, poster presentation on Monday, December 7, 2020)[Abstract #2973]
Horwitz SM, O’Connor OA, Pro B, Illidge T, Iyer SP, Advani R, Bartlett NL, Christensen JH, et al. The ECHELON-2 Trial: 5-Year Results of a Randomized, Double-Blind, Phase 3 Study of Brentuximab Vedotin and CHP (A+CHP) Versus CHOP in Frontline Treatment of Patients with CD30-Positive Peripheral T-Cell Lymphoma (Abstract #1150, poster presentation on Saturday, December 5, 2020)[Abstract #1150)

Clinical Trials
A Frontline Therapy Trial in Participants With Advanced Classical Hodgkin Lymphoma – NCT01712490
ECHELON-2: A Comparison of Brentuximab Vedotin and CHP With Standard-of-care CHOP in the Treatment of Patients With CD30-positive Mature T-cell Lymphomas – NCT01777152
An Investigational Immuno-therapy Safety and Effectiveness Study of Nivolumab in Combination With Brentuximab Vedotin to Treat Non-Hodgkin Lymphomas (CheckMate 436) – NCT02581631

Highlights of Prescribing Information
Brentuximab vedotin (Adcetris®; Seagen/Takeda)[Prescribing Information]
Nivolumab (Opdivo®; Bristol-Myers Squibb) [Prescribing Information]

Reference
[1] Radford JA, Eardley A, Woodman C, Crowther D. Follow up policy after treatment for Hodgkin’s disease: too many clinic visits and routine tests? A review of hospital records. BMJ. 1997 Feb 1;314(7077):343-6. doi: 10.1136/bmj.314.7077.343a. PMID: 9040326; PMCID: PMC2125852.
[2] Traverse-Glehen A, Pittaluga S, Gaulard P, Sorbara L, Alonso MA, Raffeld M, Jaffe ES. Mediastinal gray zone lymphoma: the missing link between classic Hodgkin’s lymphoma and mediastinal large B-cell lymphoma. Am J Surg Pathol. 2005 Nov;29(11):1411-21. doi: 10.1097/01.pas.0000180856.74572.73. PMID: 16224207.
[3] Campo E, Swerdlow SH, Harris NL, Pileri S, Stein H, Jaffe ES. The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications. Blood. 2011 May 12;117(19):5019-32. doi: 10.1182/blood-2011-01-293050. Epub 2011 Feb 7. PMID: 21300984; PMCID: PMC3109529.
[4] Pilichowska M, Pittaluga S, Ferry JA, et al. Clinicopathologic consensus study of gray zone lymphoma with features intermediate between DLBCL and classical HL. Blood Adv. December 11, 2017; 1(26):2600-2609. [Article]
[5] Kieron Dunleavy and Wyndham H. Wilson. Primary mediastinal B-cell lymphoma and mediastinal gray zone lymphoma: do they require a unique therapeutic approach?. Blood. January, 2015; 125(1):33-39.

Featured Image: An ASH attendee makes her way up a set of escalators in the Orange County Convention Center bearing signage for the support of the future of hematology during the 2017 American Society of Hematology (ASH) Annual, Meeting, and Exposition. Courtesy: © 2017 – 2020. American Society of Hematology. Used with permission.

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